Stroke is the leading cause of adult disability. However, a limited process of repair and recovery occurs after stroke. This process is associated with the formation of new neurons (neurogenesis) and the formation of new blood vessels (angiogenesis) in the tissue adjacent to the stroke. Neurogenesis and angiogenesis are intimately linked, in that newly born neurons (neuroblasts) migrate to angiogenic blood vessels in peri-infarct tissue. Both neurogenesis and angiogenesis are linked to functional recovery after stroke. The tight association of neuroblasts with angiogenic blood vessels in peri-infarct cortex forms a cellular microenvironment for tissue repair that is unique to stroke: a regenerative neurovascular niche. An understanding of the signaling molecules within the regenerative neurovascular niche may provide for novel therapies that stimulate neurogenesis, angiogenesis and functional recovery. The studies in this grant determine the mechanisms of tissue repair and recovery of candidate signaling molecules in the regenerative neurovascular niche. The PI's lab was among the first to identify this niche. The studies in this grant follow from a novel data set from the PI's lab, in which whole genome transcriptional profiling has identified the unique set of signaling molecules that interact between neuroblasts and angiogenic vessels after stroke: the regenerative neurovascular interactome. This gene set consists of all the receptor/ligand or secreted molecules that are in a position to interact between neuroblasts and their adjacent angiogenic blood vessels in peri-infarct cortex. The studies in this grant involve a systematic gain and loss of function approach to identify the candidate signaling molecules from angiogenic endothelial cell-to-neuroblast and from neuroblast-to-endothelial cell in peri-infarct cortex after stroke, using the four most important genes identified in the regenerating neurovascular interactome. These studies use novel approaches for gain and loss of function studies within the neurovascular niche, transgenic mouse lines to specifically assay the behavioral effect of enhancing neurogenesis and angiogenesis after stroke and a platform that tests the mechanistic roles of these candidate signaling systems from in vitro to in vivo to behavioral recovery studies.